Atherosclerosis causes stenosis and occlusion of arteries. Stenting and bypass surgery are often used to treat severe disease in small caliber arteries (defined as less than 6 mm in diameter). Arterial bypass procedures are limited by the availability of a vascular conduit, such as internal mammary artery or saphenous vein. Unfortunately, synthetic conduits made from polytetrafluoroethylene (PTFE) or polyethylene terephthalate (PET) suffer from unacceptably high rates of thrombosis in small caliber grafts due to their lack of an adherent, quiescent endothelium. Hence, developing a non-thrombogenic, small caliber arterial replacement has emerged as one of the most important goals of cardiovascular intervention in the elderly population.
Intravascular devices are placed within body vasculature; typically, at a site of occlusion in a vessel or the heart, or to replace or support a vessel or portion of the heart. Intravascular devices are normally manufactured from biologically inert materials intended to reduce the complications of insertion of a foreign object into the vasculature, such as stainless steel, titanium, polymers, or a combination thereof. However numerous problems have been reported to be associated with these devices, including thrombosis, neointima formation, and restenosis. Attempts have been made to reduce or eliminate the complications of intravascular devices. For example, to address the problem of thrombosis, an individual with an intravascular device may receive an anticoagulant and antiplatelet drugs, such as ticlopidin or aspirin.
One approach to overcome complications associated with intravascular devices is a strategy to promote rapid endothelialization of the surface of the device in contact with vasculature and/or blood. In that regard, U.S. Pat. No. 7,037,332 describes a medical device having a matrix coating made by cross-linking to the matrix an antibody having binding specificity for an endothelial cell antigen, for promoting attachment of endothelial cells to the medical device. U.S. Pat. No. 6,897,218 discloses metal complexes of a piperazine derivative, which are described as promoting re-endothelialization, but which do not appear to directly bind to a device, and appear to rely on large volumes of a blood-circulating composition to be effective. U.S. Pat. No. 6,140,127 describes a method of coating a stent by applying a polymer layer, applying pyridine and tresyl chloride, and applying a five amino acid peptide (glycine-arginine-glutamic acid-aspartic acid-valine; SEQ ID NO:50) for adhering cells to the stent. U.S. Pat. No. 5,929,060 discloses derivatives of the steroid DHEA, which are described as useful for re-endothelialization. U.S. Pat. No. 5,643,712 discloses coating of vessels of an organ or tissue to be grafted with a partially polymerized extracellular matrix preparation derived from endothelial cells, which may serve as a surface promoting re-endothelialization. Device design may be modified to promote the occurrence of re-endothelialization. U.S. Pat. No. 6,436,132 discloses an intraluminal prosthesis for treating a stenotic region in a blood vessel. The openings in the stent are said to allow for re-endothelialization of the blood vessel.
Cells of the endothelial cell lineage include endothelial cells and endothelial progenitor cells. Endothelial cells line all parts of the vasculature, where they regulate coagulation, inflammation, vascular permeability, and nutrient exchange between the blood and the interstitium. In areas where the endothelium is focally denuded, coagulation rapidly ensues. Focal coagulation of a blood vessel can lead to thrombosis and vascular occlusion, or other thromboembolic events. Endothelial progenitor cells have been shown to contribute to angiogenesis and vasculogenesis in a variety of model systems, and also to contribute to endothelialization of endovascular grafts in animal models. However, spontaneous endothelialization of endovascular grafts is rare in human patients, perhaps because the graft materials are engineered to resist molecular adhesion and coagulation, and endothelial progenitor cells have no ability to adhere, survive, and proliferate on such materials. Thus, there still remains a need for methods to promote endothelialization of intravascular devices such as by treating the devices so as to promote colonization and/or growth of nascent endothelium on the treated devices.
At least two types of endothelial progenitor cells can be isolated from peripheral blood: “early” endothelial progenitor cells, which live for 2 to 4 weeks in vitro and secrete potent angiogenic factors; and “late” endothelial progenitor cells, which grow out at 3 weeks and can replicate for up to 100 population doublings. Early endothelial progenitor cells are derived from bone marrow angioblasts under the influence of vascular endothelial growth factor (VEGF). Early endothelial progenitor cells have the phenotype CD133+/−, CD34+, VEGFR-2+, CD31+, vWF−, VE-cadherin−, E-selectin−, eNOS−, and telomerase+. Late endothelial progenitor cells have the phenotype CD133+/−, CD34+, VEGFR-2+, CD31+, vWF+, VE-cadherin+, E-selectin+, eNOS+, and telomerase+. Differentiated endothelial progenitor cells are similar to late endothelial progenitor cells, except that the former are CD133(−) and telomerase(−). Other endothelial progenitor cell subpopulations, and their phenotypic markers, are being described in the art.
Desired is an approach that can do one or more of attach, recruit, support, and differentiate a nascent layer of cells of endothelial cell lineage on an intravascular device surface. For example, it is desired to have an intravascular device with a coating capable of capturing circulating cells of an endothelial cell lineage so that they are seeded on the surface of an intravascular device, with the intended benefit of reducing the occurrence of complications associated with that type of intravascular device, such as one or more of thrombosis, neointima formation, and restenosis.